1. Field of the Invention
This invention relates to novel chemical processes for preparing (.alpha.S, 5S)-.alpha.-amino-3-chloro-2-isoxazoline-5-acetic acid (AT-125), (.alpha.S, 5S)-.alpha.amino-3-bromo-2-isoxazoline-5-acetic acid (bromo AT-125) and the C-5 epimers thereof. Also described are novel intermediates useful in said processes.
2. Description of the Prior Art
The heterocyclic amino acid AT-125 and a microbiological process for producing it are disclosed in U.S. Pat. Nos. 3,856,807 and 3,878,047. These patents also disclose the antitumor and antimicrobial properties of AT-125.
A process for the purification of AT-125 and production of certain AT-125 analogs generated during such process is disclosed in U.S. Pat. Nos. 4,225,720 and 4,232,164.
A multi-step chemical synthesis of AT-125 from 3,4-epoxycyclopentene is disclosed in U.S. Pat. No. 4,256,898 (see also U.S. Pat. No. 4,275,214). Also disclosed are novel analogs of AT-125 including the 3-bromo analog.
An attempt by Baldwin, et al. to synthesize AT-125 by a cycloaddition of chloronitrile oxide and vinyl glycine was unsuccessful (J. Chem. Soc. Chem. Comm., 1976, pg. 795-796). The failure of this approach was attributed to the unreactivity of chloronitrile oxide toward cycloaddition.
Recently, Hagedorn, et al., employing Baldwin's approach, have reported a one-step synthesis of the bromo analog of AT-125, i.e. ##STR1## A key feature of this synthesis, described in Tetrahedron Lett. 21:229-230 (1980), is the use of the more reactive bromonitrile oxide in place of chloronitrile oxide used by Baldwin. A serious drawback of the Hagedorn method, however, is the production of the undesired threo isomer in approximately 75% yield and the extreme difficulty of separating the erythro and threo isomers. Hagedorn, et al. report that the bromo analog of AT-125 (the erythro isomer) has antimicrobial and antitumor properties comparable to those of AT-125.
A total synthesis of AT-125 and its C-5 epimer (threo isomer) is reported by Silverman, et al. in J. Am. Chem. Soc. 103:7357-7358 (1981). Synthesis of AT-125 was carried out in eight steps fom L-erythro-.beta.-chloroglutamic acid in a 17% overall yield. The corresponding threo isomer of AT-125 was obtained in 15% overall yield from L-threo-.beta.-chloroglutamic acid.
While threo AT-125 and the corresponding threo bromo AT-125 have been disclosed in the literature, there has been no indication that these C-5 epimers possess biological activity.
In view of the promising antitumor properties reported for AT-125 and its bromo analog, it would be desirable to have a practical commercial process for chemically synthesizing these compounds from inexpensive, readily available starting materials. Such a process would also advantageously provide both the erythro and threo isomers of these compounds in substantially pure form in high yield and with substantially fewer steps than processes previously described.